Gestational diabetes mellitus (GDM) is getting more attention due to its high prevalence and adverse effects on gestational outcomes and offspring health in later life. Obesity is a key risk factor of GDM. Adipose tissue is not only metabolically active but also an endocrine organ. Adiponectin is an adipocyte-secreted hormone that improves glucose and lipid metabolism. Hypoadiponectinemia is widely observed in GDM and/or pregnant women with obesity. More importantly, human studies have demonstrated that hypoadiponectinemia before pregnancy and during the first and second trimesters strongly predicts GDM in later pregnancy. However, there is no experimental evidence verifying the causal relationship between hypoadiponectinemia and GDM. By crossing adiponectin gene knockout (Adipoq-/-) and wild-type (WT) mice, we recently created pregnant mouse models with or without adiponectin deficiency while all fetuses were genetically identical. Despite no difference in maternal body weight and adiposity, the main hallmarks of GDM, including glucose intolerance, hyperlipidemia, insulin insufficiency and increased fetal body weight, were observed in Adipoq-/- dams at late pregnancy. Viral vector-mediated adiponectin reconstitution attenuated these metabolic phenotypes in Adipoq-/- dams. Interestingly, no significant decrease in insulin sensitivity was detected in either peripheral tissues or liver of Adipoq-/- dams. However, low levels of blood insulin and reduced ?-cell mass were detected in Adipoq-/- dams. Most importantly, the above described metabolic defects were not observed in virgin Adipoq-/- mice. Our preliminary studies suggested that adiponectin enhances prolactin-induced ?-cell proliferation by increasing tryptophan hydroxylase 1 (TPH1) gene transcription and serotonin expression. Therefore, the available information and our preliminary data led us to hypothesize that adiponectin plays an important role in pregnancy-induced compensatory ?-cell expansion by enhancing TPH1/serotonin pathway. Hypoadiponectinemia impairs maternal glucose and lipid metabolism through inadequate ?-cell expansion and insulin insufficiency. A series of mouse studies is proposed under 2 specific aims. Specific aim 1 will determine the role of adiponectin in pregnancy-induced adaptive ?-cell expansion and if hypoadiponectinemia impairs maternal metabolism through insulin insufficiency. Specific aim 2 will investigate the underlying mechanisms through which adiponectin enhances pregnancy-induced ?-cell expansion. The expected results of this proposal will demonstrate the causal role of hypoadiponectinemia in the development of metabolic defects during pregnancy. The anticipated success of this project will have a significant impact on the research of maternal metabolic adaptation during normal pregnancy and GDM.